This invention relates to negative signal transduction and cell death signaling and, more specifically to the particular amino acid sequences and structures which directly mediate cell death through negative signaling.
Apoptosis is a normal physiological process of cell death that plays a critical role in the regulation of tissue homeostasis by ensuring that the rate of new cell accumulation produced by cell division is offset by a commensurate rate of cell loss due to death. It has now become clear that disturbances in apoptosis, also referred to as physiological cell death or programmed cell death, that prevent or delay normal cell turnover can be just as important to the pathogenesis of diseases as are known abnormalities in the regulation of proliferation and the cell cycle. Like cell division, which is controlled through complex interactions between cell cycle regulatory proteins, apoptosis is similarly regulated under normal circumstances by the interaction of gene products that either induce or inhibit cell death.
The stimuli which regulate the function of these apoptotic gene products include both extracellular and intracellular signals. Either the presence or the removal of a particular stimulus can be sufficient to evoke a positive or negative apoptotic signal. For example, physiological stimuli that prevent or inhibit apoptosis include, for example, growth factors, extracellular matrix, CD40 ligand, viral gene products, zinc, estrogen and androgens. In contrast, stimuli which promote apoptosis include growth factors such as tumor necrosis factor (TNF), Fas, and transforming growth factor .beta. (TGF.beta.), growth factor withdrawal, loss of extracellular matrix attachment, intracellular calcium and glucocorticoids, for example. Other stimuli, including those of environmental and pathogenetic origins, also exist which can either induce or inhibit programmed cell death. Although apoptosis is mediated by diverse signals and complex interactions of cellular gene products, the results of these interactions is thought to feed into a cell death pathway that is evolutionarily conserved between humans, other mammals and invertebrates.
Several gene products which modulate the apoptotic process have now been identified. These gene products include cell survival polypeptides such as Bcl-2, cell death polypeptides such as Bax, and cysteine aspartate proteases (caspases). The interaction and regulation of these gene products with cell surface or cytoplasmic receptors which transduce cell survival or death signals from outside the cell is as yet fairly uncharacterized. Additionally, it is unclear as to how many other genes exist which participate in apoptosis or what role they may play in the programmed cell death pathway. Finally, it also is unclear what the physiological control mechanisms are which regulate programmed cell death or how the cell death pathways interact with other physiological processes within the organism.
Thus, there exists a need for the elucidation of cell death pathways and the identification of novel molecular components which mediate apoptosis. Such molecular components can be used for the treatment or diagnosis of cell death mediated diseases. The present invention satisfies this need and provides related advantages as well.